Novel triarylimidazoles

ABSTRACT

Compounds of the general formula (I)  
                 
are presented and are valuable therapeutics for the treatment of cancer and cancer related diseases.

This invention relates to new triarylimidazoles and theirpharmaceutically acceptable salts. The compounds are protein-tyrosinekinase inhibitors, especially inhibitors of c-met kinase and aretherefore excellent therapeutics for the treatment of cancer. Theinvention relates also to pharmaceutical compositions which contain thenew compounds as active agents for the treatment of cancer and cancerrelated diseases.

BACKGROUND OF THE INVENTION

Protein-tyrosine kinases (PTKs), enzymes that catalyse the transfer ofthe y phosphate of ATP to tyrosine residues of protein substrates, arecritical components of signalling pathways that control cellularproliferation and differentiation. PTKs can be subdivided into two largefamilies, receptor tyrosine kinases (RTKs) and non-receptor tyrosinekinases (NRTKs). RTKs span the plasma membrane and contain anextra-cellular domain, which binds ligand, and an intracellular portion,which possesses catalytic activity and regulatory sequences. Most RTKs,like the hepatocyte growth factor receptor c-met possess a singlepolypeptide chain and are monomeric in the absence of ligand. Ligandbinding to the extracellular portion of RTKs, leads to dimerisation ofmonomeric receptors resulting in autophosphorylation of specifictyrosine residues in the cytoplasmic portion (for review see:Blume-Jensen, P., and Hunter, T., Nature 411 (2001) 355-365; Hubbard, S.R., et al., J. Biol. Chem. 273 (1998) 11987-11990; Zwick, E., et al.,Trends Mol. Med. 8 (2002) 17-23). In general, tyrosineautophosphorylation either stimulates the intrinsic catalytic kinaseactivity of the receptor or generates recruitment sites for downstreamsignalling proteins containing phosphotyrosine-recognition domains, suchas the Src homology 2 (SH2) domain or the phosphotyrosine-binding (PTB)domain.

Protein tyrosine kinases play a critical role in intracellular signaltransduction pathways leading to diverse cellular responses such asproliferation, apoptosis and differentiation. Consequently these enzymeshave become primary targets for the development of novel therapeuticsdesigned to block cancer cell proliferation, metastasis, angiogenesisand promote apoptosis. The strategy that has progressed farthest inclinical development is the use of monoclonal antibodies to targetgrowth factor receptor tyrosine kinases. The use of small moleculetyrosine kinase inhibitors however could have significant theoreticaladvantages over monoclonal antibodies. Small molecule inhibitors couldhave better tissue penetration, could have activity againstintracellular targets and mutated targets and could be designed to haveoral bioavailability. Several lead compounds have shown promisingactivity against such targets as the EGFR, the vascular endothelial cellgrowth factor receptor and bcr-abl.

The hepatocyte growth factor receptor c-met was first identified as anactivated oncogene in an N-methyl-N′-nitrosoguanidinc treated humanosteogenic sarcoma cell line (MUNG-HOS) by its ability to transform NIH3T3 mouse fibroblasts. The receptor encoded by the c-met protooncogene(located on chromosome 7) is a two-chain protein composed of 50 kDa(α)chain disulfide linked to a 145 kda(β) chain in an αβ complex of 190kDa. The α chain is exposed at the cell surface whilst the β chain spansthe cell membrane and possesses an intracellular tyrosine kinase domain.The presence of this intracellular tyrosine kinase domain groups c-metas a member of the receptor tyrosine kinase (RTK) family of cell surfacemolecules.

Hepatocyte growth factor (HGF), also known as Scatter Factor (SF), is amultifunctional cytokine that elicits diverse responses in differentcells and tissues. Since its initial discovery and characterisationHGF/SF has been the subject of intense research, particularly regardingits role in cancer development and progression. Much evidence now pointsto its role as a regulator of carcinogenesis, cancer invasion andmetastasis (for review see: Herynk, M. H., and Radinsky, R., In Vivo 14(2000) 587-596; Jiang, W., et al., Crit. Rev. Oncol. Hematol. 29 (1999)209-248; Longati, P., et al., Curr. Drug Targets 2 (2001) 41-55; Maulik,G., et al., Cytokine Growth Factor Rev. 13 (2002) 41-59; Parr, C., andJiang, W. G., Histol. Histopathol. 16 (2001) 251-268.

HGF/SF binds to and induces tyrosine phosphorylation of the mature c-metreceptor β chain. Such events are thought to promote binding ofintracellular signalling proteins containing src homology (SH) regionssuch as PLC-γ, Ras-GAP, PI-3 kinase pp60^(c-src) and the GRB-2 Socscomplex to the activated receptor. Each SH2-containing protein mayactivate a different subset of signalling phosphopeptides thus elicitingdifferent responses within the cell.

C-met mutations have been well-described in hereditary and sporadichuman papillary renal carcinomas and have been reported in ovariancancer, childhood hepatocellular carcinoma, metastatic head and necksquamous cell carcinomas, and gastric cancer. C-met is alsoover-expressed in both non-small cell lung cancer and small cell lungcancer cells, in breast, colon and prostate tumors. Since c-met appearsto play an important role in oncogenesis of a variety of tumors, variousinhibition strategies have been employed to therapeutically target thisreceptor tyrosine kinase.

The usefulness of inhibiting the protein-tyrosine kinase c-met forinhibiting tumor growth and invasion has been shown in many welldocumented preclinical experiments (e.g.: Abounader, R., et al., J.Natl. Cancer Inst. 91 (1999) 1548-1556; Laterra, J., et al., Lab.Invest. 76 (1997) 565-577; Tomioka, D., Cancer Res. 61 (2001) 7518-7524;Wang, R., et al., J. Cell Biol. 153 (2001) 1023-1033).

WO 96/18626 describes inhibitors of tyrosine kinases and c-met kinasewhich are derivatives of2-(2,6-dichlorophenyl)-4-phenyl-5-(pyridin-4yl)-1H-imidazole (examples5, 6 and 55). However they show unfavorable cytochrome P450interactions.

It has now been found that the compounds according to this inventionavoid this disadvantage and are potent inhibitors of c-met kinase withgood solubility.

SUMMARY OF THE INVENTION

The invention relates to compounds of the general formula (I)

wherein W, X, Y and Z are as described herewithin.

It was surprisingly found that the pharmaceutical and anti-tumorigenicactivities, due to the c-met inhibition of the compounds according tothis invention are especially provided by the presence of a2,6-dichlorophenyl or -pyridyl residue in 2-position of the imidazolering.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to new compounds of the formula

wherein

-   -   W is —N═; and    -   X is hydrogen;    -   Y is hydrogen or a group A²-R;    -   A² is C₁-C₅-alkylene, which may be optionally substituted by        C₁-C₆-alkyl; phenyl or by hydroxy;    -   R represents hydroxy; linear or branched C₁-C₆-alkoxy; amino;        dimethylamino; diethylamino; t-butyloxycarbonylamino; carboxyl;        C₁-C₆-alkoxycarbonyl; triazolyl; cyano; piperidino;        1-pyrrolidinyl; morpholino; 4-methylpiperazin-1-yl; O-A¹-NR³R⁴;        S-A¹-NR³R⁴; 4-carboxyphenyl; furan-3-yl; thiophen-2-yl or        3-methylthiophen-2-yl;    -   n is 1 or 2; and    -   Z represents one or two substituents independently selected from        the group consisting of halogen; hydroxy; allyloxy; methyl;        C₁-C₃-alkoxy, which are optionally substituted with pyridinyl;        methoxymethoxy; (2-methoxyethoxy)methyloxy; methylthio;        ethoxymethoxy; methylendioxy; ethynyl; trimethylsilylethynyl and        benzyloxy which is optionally substituted by halogen; methoxy;        cyano; nitro; methylendioxy; carboxy or ethoxy;    -   or alternatively    -   W is —CH═; and    -   X is hydrogen; OR¹; SR²; (SO)R²; (SO₂)R²;        CH₂—S—CH₂—C(O)₂—CH₂—CH₃; CH₂—S—(CH₂)₂—OH or a group A¹-Q;    -   A¹ represents a C₁-C₃-alkylene group;    -   Q is OR¹; SR²; SOR²; SO₂R²; NR³R⁴; NHCH₂CH₂NR³R⁴ or halogen;    -   R¹ is selected from the group consisting of hydrogen;        C₁-C₃-alkyl; allyl; dimethylphosphonylmethyl;        2,3-epoxy-1-propyl; (R)-2,3-dihydroxy-1-propyl;        (S)-2,3-dihydroxy-1-propyl; 1,3-dihydroxy-2-propyl;        3-hydroxy-2-hydroxymethyl-1-propyl; 2-methoxyethoxymethyl;        2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a group A¹-Q¹;    -   Q¹ represents C₁-C₂-alkoxy; cyano; carboxyl;        C₁-C₆-alkoxycarbonyl; carboxamide; —CO—NR³R⁴;        C₁-C₆-alkylsulfanyl; C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyl        and        -   in case that A¹ represents an 1,2-ethylen- or 1,3-propylen            group, Q¹ is hydroxy or NR³R⁴;    -   R² is C₁-C₆-alkyl; dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;        2,3-dihydroxy-1-propyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or        A¹-Q¹;    -   R³, R⁴ are independently selected from the group consisting of        hydrogen; C₁-C₆-alkyl or together form a 5 to 7 membered,        saturated or unsaturated ring, optionally substituted by a        methyl group and containing one or two heteroatoms,        independently selected from N or O;    -   Y is hydrogen or a group A²-R;    -   A² is C₁-C₅-alkylene, which may be optionally substituted by        C₁-C₆-alkyl; phenyl or by hydroxy;    -   R represents hydroxy; linear or branched C₁-C₆-alkoxy; amino;        dimethylamino; diethylamino; t-butyloxycarbonylamino; carboxyl;        C₁-C₆-alkoxycarbonyl; triazolyl; cyano; piperidino;        1-pyrrolidinyl; morpholino; 4-methylpiperazin-1-yl; O-A¹-NR³R⁴;        S-A¹-NR³R⁴;    -   4-carboxyphenyl; furan-3-yl; thiophen-2-yl or        3-methylthiophen-2-yl;    -   n is 1 or 2; and    -   Z represents C₁-C₃-alkoxy, substituted with pyridinyl if n is 1;        and        -   if n is 2, one substituent represents C₁-C₃-alkoxy,            substituted with pyridinyl, and the second substituent being            independently selected from the group consisting of halogen;            hydroxy; allyloxy; methyl; C₁-C₃-alkoxy; methoxymethoxy;            (2-methoxyethoxy)methyloxy; methylthio; ethoxymethoxy;            methylendioxy; ethynyl;        -   trimethylsilylethynyl; and            -   pharmaceutically acceptable salts thereof

Preferred C₁-C₆-alkyl groups with regard to R¹, R², R³, R⁴ and A² aremethyl, ethyl and propyl.

Preferred C₁-C₆-alkoxy groups with regard to Q¹, R and Z are methoxy,ethoxy or isopropyloxy.

Preferred ring systems, formed by R³ and R⁴ together represent1-pyrrolidinyl-, piperidino-, morpholino- or 4-methylpiperazin-1-yl.

Preferably X=A¹-Q represents —CH₂OH or —CH₂—CH₂—OH.

Preferably X═—O-A¹-Q¹ is —O—CH₂—CH₂—OH; —O—CH₂—COOH or —O—CH₂—CN.

Preferred groups for Y=A²-R are 2-hydroxyethyl; 3-hydroxypropyl,2-methoxyethyl; 3-methoxypropyl; (R)-2,3-dihydroxy-1-propyl;(S)-2,3-dihydroxy-1-propyl; (R)-3-hydroxybutyl; (S)-3-hydroxybutyl;2-morpholinoethyl; 3-morpholinopropyl; (CH₂)₃COOH;2-(4-methylpiperazin-1-yl)ethyl; 3-Hydroxy-2,2-dimethylpropyl;3-hydroxy-1-phenylpropyl; 3-tert-butyloxyethyl; 2-aminoethyl;3-aminopropyl; 4-aminobutyl; 2-(N,N-dimethylamino)ethyl;3-(N,N-dimethylamino)propyl; 3-(pyrrolidin-1-yl)propyl; CH₂COOH;(CH₂)₂COOH; CH(C₂H₅)COOH; (CH₂)₃COOC(CH₃)₃; (CH₂)₂—N—COOC(CH₃)₃;(CH₂)₃—N—COOC(CH₃)₃; (CH₂)₂—O—(CH₂)₂—N(CH₃)₂; (CH₂)₂—O—(CH₂)₂—NH₂;(CH₂)₂—S—(CH₂)₂—N(CH₃)₂;(CH₂)₂—S—(CH₂)₃—N(CH₃)₂;(CH₂)₃—S—(CH₂)₂—N(CH₃)₂; (CH₂)₃—S—(CH₂)₃—N(CH₃)₂;(1,2,4-triazol-1-yl)ethyl; 3-(1,2,4-triazol-3-yl)propyl; Halogen isfluorine, chlorine, bromine or iodine.

Preferably n is 1, and said substituent Z is located in the 3- or4-position. If Z represents methoxy which is substituted with pyridinyl;benzyloxy or a substituted benzyloxy group, Z is preferably located inthe 3-position.

Especially preferred are compounds of the general formula (I) andpharmaceutically acceptable salts thereof, wherein W is —N═; Z isselected from the group consisting of 3-chloro; 4-chloro; 3-bromo;3-iodo; 3-ethynyl; 3-methoxymethoxy; 3-(2-methoxyethoxy)methyloxy;3-methylthio; 3-ethoxymethoxy; 3,4-methylendioxy or 3-benzyloxy which isoptionally substituted by halogen; methoxy; cyano; nitro; methylendioxy;carboxy or ethoxy.

Also especially preferred are compounds of the general formula (I),wherein

-   -   W is —N═;    -   X is hydrogen;    -   Y represents 2-hydroxyethyl; 3-hydroxypropyl; 2-methoxyethyl;        3-methoxypropyl; (R)-2,3-dihydroxy-1-propyl;        (S)-2,3-dihydroxy-1-propyl; (R)-3-hydroxybutyl;        (S)-3-hydroxybutyl; 3-Hydroxy-2,2-dimethylpropyl;        2-morpholinoethyl; 3-morpholinopropyl;        2-(4-methylpiperazin-1-yl)ethyl; 3-hydroxy-1-phenylpropyl;        2-aminoethyl; 3-aminopropyl; 4-aminobutyl;        2-(N,N-dimethylamino)ethyl; 3-(N,N-dimethylamino)propyl;        3-(pyrrolidin-1-yl)propyl; CH₂COOH; (CH₂)₂COOH; (CH₂)₃COOH;        CH(C₂H₅)COOH; (CH₂)₂—O—(CH₂)₂—N(CH₃)₂; (CH₂)₂—O—(CH₂)₂—NH₂;        (CH₂)₂—S—(CH₂)₂—N(CH₃)₂; (CH₂)₂—S—(CH₂)₃—N(CH₃)₂;        (CH₂)₃—S—(CH₂)₂—N(CH₃)₂or (CH₂)₃—S—(CH₂)₃—N(CH₃)₂;    -   n is 1; and    -   Z is selected from the group consisting of 3-chloro; 4-chloro;        3-bromo; 3-iodo; 3-ethynyl; 3-methoxymethoxy or 3-benzyloxy        which is optionally substituted by halogen; methoxy; cyano;        nitro; methylendioxy; carboxy or ethoxy.

Also especially preferred are compounds of the general formula (I),wherein

-   -   W is —N═;    -   X is hydrogen;    -   Y is 2-hydroxyethyl; 3-hydroxypropyl;        (R)-2,3-dihydroxy-1-propyl; (S)-2,3-dihydroxy-1-propyl;        2-morpholinoethyl; 3-morpholinopropyl;        2-(4-methylpiperazin-1-yl)ethyl; 2-aminoethyl; 3-aminopropyl;        2-(N,N-dimethylamino)ethyl; 3-(N,N-dimethylamino)propyl or        3-(pyrrolidin-1-yl)propyl;    -   n is 1; and    -   Z is selected from the group consisting of 3-chloro; 4-chloro;        3-bromo; 3-iodo; 3-ethynyl; 3-methoxymethoxy or        -   3-benzyloxy which is optionally substituted by halogen;            methoxy or cyano.

Such a compound is for example:

-   -   2-(3,5-dichloropyridin-4-yl)-4-(3-benzyloxyphenyl)-5-(2-[3-hydroxypropyl-amino]pyrimidin-4-yl)-N-1H-imidazole

A further embodiment of the present invention are the compounds offormula (I), wherein

-   -   W is —CH═;    -   X is hydrogen; OR¹; SR²; (SO)R²; (SO₂)R²;        CH₂—S—CH₂—C(O)₂—CH₂—CH₃; CH₂—S—(CH₂)₂—OH or a group A¹-Q;    -   A¹ represents a C₁-C₃-alkylen group;    -   Q is OR¹; SR²; SOR²; SO₂R²; NR³R⁴; NHCH₂CH₂NR³R⁴ or halogen;    -   R¹ is selected from the group consisting of hydrogen;        C₁-C₃-alkyl; allyl; dimethylphosphonylmethyl;        2,3-epoxy-1-propyl; (R)-2,3-dihydroxy-1-propyl;        (S)-2,3-dihydroxy-1-propyl; 1,3-dihydroxy-2-propyl;        3-hydroxy-2-hydroxymethyl-1-propyl; 2-methoxyethoxymethyl;        2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a group A¹-Q¹;    -   Q¹ represents C₁-C₂-alkoxy; cyano; carboxyl;        C₁-C₆-alkoxycarbonyl; carboxamide; —CO—NR³R⁴;        C₁-C₆-alkylsulfanyl; C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyl        and        -   in case that A¹ represents an 1,2-ethylen- or 1,3-propylen            group, Q¹ is hydroxy or NR³R⁴;    -   R² is C₁-C₆-alkyl; dimethylphosphonylmethyl; 2,3-epoxy-i-propyl;        2,3-dihydroxy-1-propyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or        A¹-Q¹;    -   R³, R⁴ are independently selected from the group consisting of        hydrogen; C₁-C₆-alkyl or together form a 5 to 7 membered,        saturated or unsaturated ring, optionally substituted by a        methyl group and containing one or two heteroatoms,        independently selected from N or O;    -   Y is 3-hydroxypropyl; and    -   Z is 3-benzyloxy which is optionally substituted by halogen;        methoxy or cyano.

Still another embodiment of the invention are the compounds of formula(I), wherein

-   -   W is —CH═;    -   X is hydrogen; or OR¹;    -   R¹ is selected from the group consisting of hydrogen;        C₁-C₃-alkyl; allyl; dimethylphosphonylmethyl;        2,3-epoxy-1-propyl; (R)-2,3-dihydroxy-1-propyl;        (S)-2,3-dihydroxy-1-propyl; 1,3-dihydroxy-2-propyl;        3-hydroxy-2-hydroxymethyl-1-propyl; 2-methoxyethoxymethyl;        2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a group A¹-Q¹;    -   A¹ represents a C₁-C₃-alkylen group;    -   Q¹ represents C₁-C₂-alkoxy; cyano; carboxyl;        C₁-C₆-alkoxycarbonyl; carboxamide; C₁-C₆-alkylsulfanyl;        C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyl and        -   in case that A¹ represents an 1,2-ethylen- or 1,3-propylen            group, Q¹ is hydroxy;    -   Y is 3-hydroxypropyl; and    -   Z is 3-benzyloxy.

A further embodiment of the present invention are the compounds offormula (I), wherein

-   -   W is —CH═;    -   X is hydrogen; OR¹; SR²; (SO)R²; (SO₂)R²;        CH₂—S—CH₂—C(O)₂—CH₂—CH₃; CH₂—S—(CH₂)₂—OH or a group A¹-Q;    -   A¹ represents a C₁-C₃-alkylene group;    -   Q is OR¹; SR²; SOR²; SO₂R²; NR³R⁴; NHCH₂CH₂NR³R⁴ or halogen;    -   R¹ is selected from the group consisting of hydrogen;        C₁-C₃-alkyl; allyl; dimethylphosphonylmethyl;        2,3-epoxy-1-propyl; (R)-2,3-dihydroxy-1-propyl;        (S)-2,3-dihydroxy-1-propyl; 1,3-dihydroxy-2-propyl;        3-hydroxy-2-hydroxymethyl-1-propyl; 2-methoxyethoxymethyl;        2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a group A¹-Q¹;    -   Q¹ represents C₁-C₂-alkoxy; cyano; carboxyl;        C₁-C₆-alkoxycarbonyl; carboxamide; —CO—NR³R⁴;        C₁-C₆-alkylsulfanyl; C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyl        and        -   in case that A¹ represents an 1,2-ethylen- or 1,3-propylen            group, Q¹ is hydroxy or NR³R⁴;    -   R² is C₁-C₆-alkyl; dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;        2,3-dihydroxy-1-propyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or        A¹-Q¹;    -   R³, R⁴ are independently selected from the group consisting of        hydrogen; C₁-C₆-alkyl or together form a 5 to 7 membered,        saturated or unsaturated ring, optionally substituted by a        methyl group and containing one or two heteroatoms,        independently selected from N or O;    -   Y is hydrogen or a group A²-R;    -   A² is C₁-C₅-alkylene, which may be optionally substituted by        C₁-C₆-alkyl; phenyl or by hydroxy;    -   R represents hydroxy; linear or branched C₁-C₆-alkoxy; amino;        dimethylamino; diethylamino; t-butyloxycarbonylamino; carboxyl;        C₁-C₆-alkoxycarbonyl; triazolyl; cyano; piperidino;        1-pyrrolidinyl; morpholino; 4-methylpiperazin-1-yl; O-A¹-NR³R⁴;        S-A¹-NR³R⁴;    -   4-carboxyphenyl; furan-3-yl; thiophen-2-yl or        3-methylthiophen-2-yl;    -   n is 1; and    -   Z represents C₁-C₃-alkoxy, which is substituted with pyridinyl.

Still another embodiment of the present invention are the compounds offormula (I), wherein

-   -   W is —CH═;    -   X is hydrogen; OR¹; SR²; (SO)R²; (SO₂)R²;        CH₂—S—CH₂—C(O)₂—CH₂—CH₃; CH₂—S—(CH₂)₂—OH or a group A¹-Q;    -   A¹ represents a C₁-C₃-alkylene group;    -   Q is OR¹; SR²; SOR²; SO₂R²; NR³R⁴; NHCH₂CH₂NR³R⁴ or halogen;    -   R¹is selected from the group consisting of hydrogen;        C₁-C₃-alkyl; allyl; dimethylphosphonylmethyl;        2,3-epoxy-1-propyl; (R)-2,3-dihydroxy-1-propyl;        (S)-2,3-dihydroxy-1-propyl; 1,3-dihydroxy-2-propyl;        3-hydroxy-2-hydroxymethyl-1-propyl; 2-methoxyethoxymethyl;        2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a group A¹-Q¹;    -   Q¹ represents C₁-C₂-alkoxy; cyano; carboxyl;        C₁-C₆-alkoxycarbonyl; carboxamide; —CO—NR³R⁴;        C₁-C₆-alkylsulfanyl; C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyl        and        -   in case that A¹ represents an 1,2-ethylen- or 1,3-propylen            group, Q¹ is hydroxy or NR³R⁴;    -   R² is C₁-C₆-alkyl; dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;        2,3-dihydroxy-1-propyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or        A¹-Q¹;    -   R³, R⁴ are independently selected from the group consisting of        hydrogen; C₁-C₆-alkyl or together form a 5 to 7 membered,        saturated or unsaturated ring, optionally substituted by a        methyl group and containing one or two heteroatoms,        independently selected from N or O;    -   Y is 3-hydroxypropyl;    -   n is 1; and    -   Z is pyridin-2-ylmethoxy; pyridin-3-ylmethoxy or        pyridin-4-ylmethoxy.

Such compounds are for example:

-   2-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(4-pyridinylmethyloxy)phenyl)-5-(2-[3-hydroxypropylamino]pyrimidin-4-yl)-N-1H-imidazole,-   2-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(3-pyridinylmethyloxy)phenyl)-5-(2-[3-hydroxypropylamino]pyrimidin-4-yl)-N-1H-imidazole,    and-   2-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(2-pyridinylmethyloxy)phenyl)-5-(2-[3-hydroxypropylamino]pyrimidin-4-yl)-N-1H-imidazole.

Formula (I) represents2-(2,6-dichlorophenyl)-4-phenyl-5-(4-pyrimidinyl)-1H-imidazoles whichare the tautomers of2-(2,6-dichlorophenyl)-5-phenyl-4-(4-pyrimidinyl)-1H-imidazoles. Bothtautomers represent the same structure, their nomenclature may be usedinterchangeably and both tautomers are part of the invention. Thecompounds of the present invention may contain one or more asymmetriccarbon atoms and may occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers, including opticalisomers, being included within the scope of the present invention.

Compounds of the general formula (I) can be prepared by reacting acompound of the general formula (VI) or (VII) with an amine Y—NH₂,wherein W, X, Y, n and Z have the significance as defined herein before,at a temperature in the range of 80 to 180° C. and subsequent isolationof said compound. Preferably stoichiometric amounts or an excess of saidamines are used. The reaction can be performed without solvent or in asolvent like dioxane, dimethoxyethane or toluene.

Compounds of the general formula (VI) and (VII) can be obtained byoxidation of the sulfide group of the thioethers, described by thegeneral formula (V). To obtain the sulfoxides of the general formula(VI) the oxidation is preferably carried out by using 3-chloroperbenzoicacid. For the synthesis of the sulfones of the general formula (VII)oxone™ is preferably used.

The thioethers of the general formula (V)

can be obtained by N-deoxygenation of compounds of the general formula(IV). This reaction is preferably carried out using ethyl bromoacetatein the presence of triethylamine (Somei, M., and Tsuchiya, M., Chem.Pharm. Bull. 29 (1981) 3145-3157). Alternatively, this reduction can beachieved by the use of triethylphosphite in dimethylformamide.

A compound of the general formula (IV) can be obtained by reacting acompound of the general formula (III) with a compound of the generalformula (II), wherein the substituents W, X and Z have the significanceas defined hereinbefore. This reaction is a condensation and ispreferably carried out in the presence of ammonia, using methods whichare known for other aldehydes.

A further embodiment of the invention is the use of a compound of thegeneral formula (II), wherein the substituent X has the significance asdefined hereinbefore, for the manufacture of a compound of the generalformula (I) as described in the above-mentioned process.

The 2,6-dichlorobenzaldehydes are valuable intermediates for themanufacture of the compounds of the general formula (I) according to theinvention. 2,6-dichloro-3-hydroxybenzaldehyde and2,6-dichloro-4-hydroxybenzaldehyde are known from the state of the art.The 2,6-dichloro-3-hydroxybenzaldehyde has been synthesized from3-hydroxybenzaldehyde (Gust, R., and Schoenenberg, H., Eur. J. Med.Chem. 28 (1993) 103-115), but this requires the use of highly toxicchlorine gas and leads to side products because of overoxidation. Theprocedure disclosed in this invention (example A2) avoids thesedisadvantages. 2,6-dichloro-4-hydroxybenzaldehyde can be prepared from3,5-dichlorophenol by either a Reimer-Tiemann reaction (Baldwin, J. J.,et al., J. Med. Chem. 22 (1979) 687-693) or by a bromination/Grignardsequence (WO 01/44154). The Reimer-Tiemann procedure does not allow aneconomically preparation due to very low yields (<4%); in addition, therequired use of chloroform causes substantial ecological issues. Theother known reaction via a bromination/Grignard sequence requires 4steps totally, including stoichiometric bromination with bromine and theuse of toxic chloromethyl methyl ether to protect the phenol. Inaddition, the total yield is only 40%.

This invention provides an improved process for the manufacture of2,6-dichloro-3-hydroxybenzaldehyde and2,6-dichloro-4-hydroxybenzaldehyde. This process is characterized by themetallation of protected 2,4-dichlorophenol or 3,5-dichlorophenol with alithium base, followed by reaction with an ester or amide of formic acidand the deprotection and isolation of said compounds. A suitable lithiumbase is methyllithium, n-butyllithium, sec-butyllithium, t-butyllithium,lithiumdiisopropylamide or lithium bistrimethylsilylamide, prefered isbutyllithium. An appropriate solvent is diethyl ether, tetrahydrofuraneor 1,2-dimethoxyethane, preferred is tetrahydrofurane. The metallationstep is performed at −100° C. to 60° C., preferably at −80° C. to −70°C. Suitable protecting groups are triisopropylsilanyl,t-butyldimethylsilanyl or phenyldimethylsilanyl, prefered istriiso-propylsilanyl. Suitable derivatives of formic acid are methylformate, ethylformate, dimethylformamide or N-formylpiperidine,preferred is dimethylformamide. This procedure can also be applied forthe manufacture of 2,6-dichloro-3-hydroxymethylbenzaldehyde and2,6-dichloro-4-hydroxymethyl-benzaldehyde according to this invention.

The term “pharmaceutically acceptable salt” as used herein before refersto conventional acid-addition salts or base-addition salts that retainthe biological effectiveness and properties of the compounds of formula(I) and are formed from suitable non-toxic organic or inorganic acids ororganic or inorganic bases. Sample acid-addition salts include thosederived from inorganic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid andnitric acid, and those derived from organic acids such asp-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalicacid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid,and the like. Sample base-addition salts include those derived fromammonium, potassium, sodium and, quaternary ammonium hydroxides, such asfor example, tetramethylammonium hydroxide. The chemical modification ofa pharmaceutical compound (i.e., a drug) into a salt is a technique wellknown to pharmaceutical chemists to obtain improved physical andchemical stability, hygroscopicity, flowability and solubility ofcompounds (see, e.g., H. Ansel et. al., Pharmaceutical Dosage Forms andDrug Delivery Systems, 6th ed., (1995), pp. 196 and 1456-1457.

The compounds of formula (I) and the pharmaceutically acceptable saltsof the compounds of formula (I) can be used as medicaments, e.g. in theform of pharmaceutical preparations. The pharmaceutical preparations canbe administered orally, e.g., in the form of tablets, coated tablets,dragées, hard and soft gelatine capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, parenterally, e.g. in the form ofinjection solutions.

The compounds of formula (I) can be processed with pharmaceuticallyinert, inorganic or organic carriers for the production ofpharmaceutical preparations. Lactose, corn starch or derivativesthereof, talc, stearic acids or its salts and the like can be used, forexample, as such carriers for tablets, coated tablets, dragées and hardgelatine capsules. Suitable carriers for soft gelatine capsules are, forexample, vegetable oils, waxes, fats, semi-solid and liquid polyols andthe like. Depending on the nature of the active substance no carriersare, however, usually required in the case of soft gelatine capsules.Suitable carriers for the production of solutions and syrups are, forexample, water, polyols, glycerol, vegetable oil and the like. Suitablecarriers for suppositories are, for example, natural or hardened oils,waxes, fats, semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

Medicaments containing a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a therapeutically inert carrier are also anobject of the present invention, as is a process for their production,which comprises bringing one or more compounds of formula (I) and/orpharmaceutically acceptable salts and, if desired, one or more othertherapeutically valuable substances into a galenical administration formtogether with one or more therapeutically inert carriers.

Because of their activity as tyrosine kinase inhibitors, preferably ofc-met kinase, compounds of the general formula (I) are valuableingredients of therapeutics aiming at the treatment of cancer and otherdiseases that correspond with enhanced expression of the c-met receptoror related kinase receptors.

Therefore the dosage of a compound according to this invention can varywithin wide limits and will also have to be adjusted to the individualrequirements in each particular case. In the case of oral administrationthe dosage for adults can vary from about 0.01 mg to about 1000 mg perday of a compound of general formula (I) or of the corresponding amountof a pharmaceutically acceptable salt thereof. The daily dosage may beadministered as single dose or in divided doses and, in addition, theupper limit can also be exceeded when this is found to be indicated.

The following examples and preparations illustrate the invention but arenot intended to limit its scope.

EXAMPLES A Synthesis of substituted 2,6-dichlorobenzaldehydes Example A12,6-dichloro-4-hydroxybenzaldehyde (A1) Preparation of3,5-dichlorotriisopropylsilyloxybenzene (A1.1)

To a solution of 200 g 3,5-dichlorophenol and 330 ml 2,6-lutidine in 3.01 dry CH₂Cl₂ 400 g triisopropyl-silyltriflate was added at 0° C. within1 h and the mixture was stirred for additional 3 hours at thistemperature. After hydrolysis with 1.0 l water the organic layer waswashed with saturated NaCl, dried over MgSO₄ and evaporated to dryness(70° C./80 mbar). The residue was taken up in petroleum ether andfiltrated through Silica to yield 360 g (92%) A1.1 as colorless oil.

¹H-NMR (250 MHz, CDCl₃) δ=1.03-1.15 (m, 18 H, CH₃); 1.16-1.35 (m, 3 HCH); 6.73-6.80 (m, 2 H, CH_(arom.)); 6.92-6.98 (m, 1 H, CH_(arom.))

¹³C-NMR (62.9 MHz, CDCl₃) δ=12.7 (CH); 18.0 (CH3); 119.0, 121.6(CH_(arom.)); 135.2, 157.4 (C_(arom.))

Preparation of 2,6-dichloro-4-hydroxybenzaldehyde (A1) and2,6-dichloro-4-triisopropylsilyloxy-benzaldehyde (A1.2)

To a solution of 360 g A1.1 in 2.6 l dry tetrahydrofuran 440 ml n-BuLi(2.7 M in hexane) was added under nitrogen keeping the temperature below−65° C. After stirring for 2 h at −70° C. 120 ml dry dimethylformamidewas added keeping the temperature below 65° C. The mixture was allowedto warm up to room temperature overnight. After addition of 700 ml 4 MHCl the mixture was stirred vigorously for 1 h at room temperature. Thenthe phases were separated (addition of solid NaCl may be necessary) andthe organic layer was dried over sodium sulphate and was reduced invacuo. Recrystallization of the precipitate from toluene/tetrahydrofuranyielded 154 g (70%) Al, m.p. 229-230° C.

¹H-NMR (250 MHz, DMSO-D₆) δ=6.94 (s, 2 H, CH_(arom.)); 10.25 (s, 1 H,CH═O), 11.46 (s (br), 1 H, OH)

¹³C-NMR (62.9 MHz, DMSO-D₆) δ=117.0 (CH_(arom.)); 120.7, 137.8, 162.1(C_(arom.)); 187.2 (CH═O)

Example A2 Preparation of ethyl (3,5-dichloro-4-formylphenoxy)acetate(A2)

A mixture of 2.87 g (15 mmol) A1, 2.76 g (16.5 mmol) ethyl bromoacetateand 2.90 g (21 mmol) potassium carbonate in 50 ml dry acetone werestirred for 3 h at 60° C. After filtration and removal of the solventthe residue was purified by column chromatography on Silica (ethylacetate/methanol 100:2). Yield: 3.5.5 g (86 %) A2, colorless solid.

¹H-NMR (250 MHz, CDCl₃): δ=1.32 (t, 7.2 Hz, 3 H, CH₃); 4.30 (q, 7.2 Hz,2 H, CH₂); 4.68 (s, 2 H, CH₂); 6.92 (s, 2 H, CH_(arom.)); 10.41 (s, 1 H,CH═O).

¹³C-NMR (62.9 MHz, CDCl₃): δ=14.3 (CH₃); 62.1, 65.5 (CH₂); 116.4(CH_(arom.)); 123.8, 139.2, 160.9 (C_(arom.)); 167.3 (C═O); 187.8(CH═O).

B Synthesis of the “Weinreb”-Type Amides Example B13-benzyloxy-N-methoxy-N-methylbenzamide (B1)

To a suspension of 136.8 g (0.60 mol) 3-benzyloxybenzoic acid in 1200 mldichloromethane 60.6 g (0.6 mol) triethylamine was added at 10° C. Asolution of 64.8 g (0.60 mol) ethyl chloroformiate in 100 mldichloromethane was added over a period of 15 minutes keeping thetemperature between 10° C. and 15° C. After stirring for 40 minutes andaddition of 58.2 g (0.60 mol) N,O-dimethylhydroxylamine hydrochloride asolution of 60.6 g (0.60 mol) triethylamine was added over a period of20 minutes at 10-15° C. After additional strirring for 30 minutes waterwas added and the organic layer dried over sodium sulphate. Fractionateddistillation in vacuo yielded 131.9 g (81%) B1.

MS: 273 (API+)

Example B2 3-hydroxy-N-methoxy-N-methylbenzamide (B2)

To a solution of 100 g (0.37 mol) B1 in 750 ml tetrahydrofuran 10 g Pd/C(10%) were added and the mixture was hydrogenated at atmosphericpressure for 2 hours. The catalyst was filtered off and the filtrate wasevaporated to yield 66.0 g B2 (98%).

MS: 182 (API+), 180 (API−)

Example B3 3-(2-pyridinylmethyloxy)-N-methoxy-N-methylbenzamide (B3)

To a solution of 1.21 g (10.0 mmol) B2, 2.89 g (11.0 mmol)triphenylphosphine and 1.20 g (11.0 mmol) pyridine-2-methanol in 30 mldry tetrahydrofuran a solution of 1.92 g (11.0 mmol) diethylazodicarboxylate in 5 ml dry tetrahydrofuran was added and the mixturewas stirred at room temperature for 2 hours. After removal of thesolvent and column chromatography on Silica (hexane/ethyl acetate 2:1)2.81 g B3 were obtained as a light yellow oil (72% yield assuming 30 mol% impurity of triphenylphosphine oxide (measured by NMR)). Due to theproblems with the separation of the impurities in this particularexample the experiment was repeated with PS-bound triphenylphosphine togive pure B3 in 58% yield.

MS: M=273 (API+)

¹H-NMR (400 MHz, CDCl₃) δ=3.25 (s, 3H, CH₃); 3.45 (s, 3H, OCH₃); 5.15(s, 2H, OCH₂); 6.98-7.04 (m, 1H); 7.12-7.28 (m, 4H); 7.40-7.48 (m, 1H);7.60-7.68 (m, 1H); 8.46-8.56 (m, 1H).

¹³C-NMR (100.6 MHz, CDCl₃) δ=34.3 (CH₃); 61.5 (OCH₃); 71.0 (OCH₂);114.9, 117.6, 121.3, 121.8, 123.2, 129.7, 135.9*, 137.3, 149.6, 157.3*,158.3* (C_(arom)H); 169.9 (C═O). (*=quatery carbon)

Example B4 3-(3-pyridinylmethyloxy)-N-methoxy-N-methylbenzamide (B4)

An analogous reaction to that described in example B3 but reacting with3-pyridinylmethanol gave B4 in 81% yield.

MS: M=273 (API+)

¹H-NMR (400 MHz, DMSO-D₆) δ=3.24 (s, 3H, CH₃); 3.53 (s, 3H, OCH₃); 5.20(s, 2H, OCH₂); 7.12-7.24 (m, 3H); 7.34-7.48 (m, 2H); 7.84-7.92 (m, 1H);8.52-8.60 (m, 1H); 8.68-8.72 (m, 1H).

¹³C-NMR (100.6 MHz, DMSO-D₆) δ=33.7 (CH₃); 61.1 (OCH₃); 67.4 (OCH₂);114.1, 117.3, 120.5, 124.0, 129.7, 132.8, 136.1, 136.2, 149.5, 149.6,157.9 (C_(arom)H); 169.0 (C═O).

Example B5 3-(4-pyridinylmethyloxy)-N-methoxy-N-methylbenzamide (B5)

An analogous reaction to that described in example B3 but reacting with4-pyridinylmethanol gave B5 in 82% yield.

MS: M=273 (API+)

¹H-NMR (400 MHz, DMSO-D₆) δ=3.24 (s, 3H, CH₃); 3.51 (s, 3H, OCH₃); 5.24(s, 2H, OCH₂); 7.12-7.22 (m, 3H); 7.34-7.41 (m, 1H); 7.42-7.48 (m, 2H);8.52-8.64 (m, 2H).

¹³C-NMR (100.6 MHz, DMSO-D₆) δ=33.7 (CH₃); 61.0 (OCH₃); 67.9 (OCH₂);114.1, 117.3, 120.7, 122.1, 129.8, 136.3, 146.4, 150.1, 157.7(C_(arom)H); 169.0 (C═O).

C Synthesis of the “Ethanones” Example C11-(3-(2-pyridinylmethyloxy)phenyl)-2-(2-methylthiopyrimidin-4-yl)-ethanone(C1)

2.1 ml (15 mmol) diisopropylamine were dissolved in 70 ml drytetrahydrofuran and cooled to −75° C. and 9.4 ml of a solution ofn-butyllithium (1.6 M, 15 mmol) were added over a period of 10 minutes.After stirring for 15 minutes at −75° C. a solution of 1.69 g (12 mmol)2-methylthio-4-methylpyrimidine in 5 ml dry tetrahydrofuran was addedwithin 10 minutes at −75° C. and the mixture was stirred for additional15 minutes. Then a solution of 2.73 g (7 mmol) B3 (70% purity) in 5 mldry tetrahydrofuran was added within 10 minutes at −75° C. The mixturewas stirred for one hour at −75° C. and then allowed to warm up to roomtemperature and finally poured on 100 ml ethyl acetate/water (1:1). Theaqueous layer was extracted with 50 ml ethyl acetate and the combinedorganic layers were dried over sodium sulphate. Removal of the solventin vacuo and column chromatography on Silica (n-heptane/ethyl acetate3:1) yielded 1.52 g (62%) C1. (keto-enole ratio measured by NMR in CDCl3at 400 MHz is about 30:70).

MS: M=352 (API+), 350 (API−)

Example C21-(3-(3-pyridinylmethyloxy)phenyl)-2-(2-methylthiopyrimidin-4-yl)-ethanone(C2)

An analogous reaction to that described in example C1 but starting withB4 gave C2 in 60% yield

MS: M=352 (API+), 350 (API−)

Example C31-(3-(4-pyridinylmethyloxy)phenyl)-2-(2-methylthiopyrimidin-4-yl)-ethanone(C3)

An analogous reaction to that described in example C1 but starting withB5 gave C3 in 55 % yield

MS: M=352 (API+), 350 (API−)

Example C4 1-(3-benzyloxyphenyl)-2-(2-methylthiopyrimidin-4-yl)-ethanone(C4)

An analogous reaction to that described in example C1 but starting withB1 gave C4 in 89 % yield

MS: M=351 (API+), 349 (API−)

D Synthesis of the “Ketoximes” Example D11-(3-(2-pyridinylmethyloxy)phenyl)-2-(2-methylthiopyrimidin-4-yl)-2-hydroxy-iminoethanone(D1)

1.50 g (4.3 mmol) C1 were dissolved in a mixture of 18.6 ml glacialacid, 15.0 ml tetrahydrofuran and 2.0 ml water. After cooling to 5° C. asolution of 353 mg (5.1 mmol) sodium nitrite in 3.5 ml water was addedkeeping the temperature between 5° C. and 10° C. The cooling was removedand the mixture stirred for 2 hours at room temperature. After removalof the solvent in vacuo 35 ml water and 240 ml ethyl acetate were added.The pH was adjusted to 8 with 3 N NaOH. The phases were separated andthe aqueous layer was extracted with 50 ml ethyl acetate. The combinedorganic layers were dried over sodium sulphate and the solvent wasremoved in vacuo. Yield: 1.61 g (99%) D1,

MS: M=381 (API+), 379 (API−)

¹H-NMR (400 MHz, DMSO-D₆) δ=2.17 (s, 3H, SCH3); 5.25 (s, 2H, OCH₂);7.30-7.35 (m, 1H); 7.36-7.42 (m, 3H); 7.47-7.54 (m, 2H); 7.62-7.65 (m,1H); 7.78-7.85 (m, 1H); 8.52-8.55 (m, 1H); 8.68-8.72 (m, 1H); 12.80 (br,1H, OH).

¹³C-NMR (100.6 MHz, DMSO-D₆) δ=13.6 (SCH₃); 70.9 (OCH₂); 111.7, 113.8,121.6, 122.0 122.1, 123.4, 131.0, 136.4*, 137.3, 149.5, 154.0*, 156.5*,158.7, 158.9*, 159.3*, 171.8; 193.3*

(C═O). (=quatery carbon)

Example D21-(3-(3-pyridinylmethyloxy)phenyl)-2-(2-methylthiopyrimidin-4-yl)-2-hydroxy-iminoethanone(D2)

An analogous reaction to that described in example C1 but starting withC2 gave D2 in 92% yield.

MS: M=381 (API+), 379 (API−)

¹H-NMR (400 MHz, DMSO-D₆) δ=2.19 (s, 3H, SCH₃); 5.23 (s, 2H, OCH₂);7.32-7.46 (m, 4H); 7.46-7.56 (m, 1H); 7.58-7.68 (m, 1H); 7.84-7.92 (m,1H); 8.50-8.56 (m, 1H); 8.64-8.72 (m, 2H).

Example D31-(3-(4-pyridinylmethyloxy)phenyl)-2-(2-methylthiopyrimidin-4-yl)-2-hydroxy-iminoethanone(D3)

An analogous reaction to that described in example C1 but starting withC3 gave D3 in 97% yield.

MS: M=381 (API+), 379 (API−)

¹H-NMR (400 MHz, DMSO-D₆) δ=2.18 (s, 3H, SCH₃); 5.27 (s, 2H, OCH₂);7.36-7.43 (m, 3H); 7.43-7.49 (m, 2H); 7.49-7.55 (m, 1H); 7.61-7.68 (m,1H); 8.54-8.63 (m, 2H), 8.68-8.74 (m, 1H); 12.78 (s, 1H, OH).

Example D41-(3-benzyloxyphenyl)-2-(2-methylthiopyrimidin-4-yl)-2-hydroxyiminoethanone(D4)

An analogous reaction to that described in example C1 but starting withC4 gave D4 in 86% yield.

MS: M=380 (API+), 378 (API−)

¹H-NMR (250 MHz, DMSO-D₆) δ=2.19 (s, 3H SCH₃); 5.17 (s, 2H, OCH₂);7.24-7.53 (m, 9H); 7.59-7.69 (m, 1H); 8.63-8.72 (m, 1H); 12.83 (br, 1H,OH).

¹³C-NMR (62.9 MHz, DMSO-D₆) δ=13.6 (SCH₃); 69.9 (OCH₂); 111.7, 113.7,121.6, 122.1, 128.1, 128.3, 128.8, 130.9, 136.5*, 136.9*, 154.0*, 158.6,159.1*, 159.4*, 171.8*; 193.5* (C═O).

(*=quatery carbon)

E Synthesis of the “N-hydroxy Imidazoles” Example E12-(2,6-dichloro-4-[ethoxycarbonylmethoxy]phenyl)-4-(3-(2-pyridinylmethyl-oxy)phenyl)-5-(2-methylthiopyrimidin-4-yl)-N-hydroxy-imidazole(E1)

A mixture of 1.60 g (4.2 mmol) D1, 1.40 g (5.0 mmol) A2 and 3.25 g (42mmol) ammonium acetate in 40 ml acetic acid was stirred at 105° C. for3.5 hours. The solvent was distilled off and the residue waspartitionated between 40 ml ice water and 60 ml ethyl acetate andadjusted to pH 8 with conc. aqueous ammonia. The aqueous layer wasextracted with ethyl acetate and the combined organic layers were driedover MgSO₄ and evaporated to dryness to yield 3.60 g of a light brown,slowly solidifying oil which was used for the next step (example F1)without further purification.

MS: M=638 (API+), 636 (API−)

Example E22-(2,6-dichloro-4-[ethoxycarbonylmethoxy]phenyl)-4-(3-(3-pyridinylmethyl-oxy)phenyl)-5-(2-methylthiopyrimidin-4-yl)-N-hydroxy-imidazole(E2)

An analogous reaction to that described in example E1 but starting withD2 yielded E2 as an orange oil.

MS: M=638 (API+), 636 (API−)

Example E32-(2,6-dichloro-4-[ethoxycarbonylmethoxy]phenyl)-4-(3-(4-pyridinylmethyl-oxy)phenyl)-5-(2-methylthiopyrimidin-4-yl)-N-hydroxy-imidazole(E3)

An analogous reaction to that described in example E1 but starting withD3 yielded E3 as a yellow solid.

MS: M=638 (API+), 636 (API−)

Example E42-(3,5-dichloropyridin-4-yl)-4-(3-benzyloxyphenyl)-5-(2-methylthiopyrimidin-4-yl)-N-hydroxy-imidazole(E4)

An analogous reaction to that described in example E1 but starting withD4 and 3,5-dichloropyridine-4-carboxaldehyde (J. Med. Chem. 44 (2001)997) yielded E4 as a orange solid.

MS: M=536 (API+), 534 (API−)

F Synthesis of the “N—H Imidazoles” Example F12-(2,6-dichloro-4-[methoxycarbonylmethoxy]phenyl)-4-(3-(2-pyridinylmethyl-oxy)phenyl)-5-(2-methylthiopyrimidin-4-yl)-N—H-imidazole(F1)

A mixture of 3.59 g (4.2 mmol) E1, 1.41 g (8.4 mmol) methyl bromoacetateand 2.85 g (28 mmol) triethylamine in 80 ml methanol was stirredovernight at 60° C. After removal of the solvent in vacuo columnchromatography on silica (ethyl acetate/iso-hexane 3:1) returned 2.08 g(81%) pure F1 (transesterification in methanol).

MS: M=608 (API+), 606 (API−)

Example F22-(2,6-dichloro-4-[methoxycarbonylmethoxy]phenyl)-4-(3-(3-pyridinylmethyl-oxy)phenyl)-5-(2-methylthiopyrimidin-4-yl)-N—H-imidazole(F2)

An analogous reaction to that described in example F1 but starting withE2 yielded 65% F2.

MS: M=608 (API+), 606 (API−)

Example F32-(2,6-dichloro-4-[methoxycarbonylmethoxy]phenyl)-4-(3-(4-pyridinylmethyl-oxy)phenyl)-5-(2-methylthiopyrimidin-4-yl)-N—H-imidazole(F3)

An analogous reaction to that described in example F1 but starting withE3 yielded 66% F3.

MS: M=608 (API+), 606 (API−)

Example F42-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(2-pyridinylmethyloxy)phenyl)-5-(2-methylthiopyrimidin-4-yl)-N—H-imidazole(F4)

To a solution of 2.07 g (3.3 mmol) F1 in 50 ml dry THF under nitrogenLiAlH₄ (1M in THF) was added at 0° C. until F1 could no longer bedetected by HPLC. After hydrolysis with 0.5 ml water and removal of thesolvent the residue was purified by column chromatography on silica(ethyl acetate/methanol 9:1) to yield 93% F4.

MS: M=580 (API+), 578 (API−)

Example F52-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(3-pyridinylmethyloxy)phenyl)-5-(2-methylthiopyrimidin-4-yl)-N—H-imidazole(F5)

An analogous reaction to that described in example F4 but starting withF2 yielded 64% F5.

MS: M=580 (API+), 578 (API−)

Example F62-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(4-pyridinylmethyloxy)phenyl)-5-(2-methylthiopyrimidin-4-yl)-N—H-imidazole(F6)

An analogous reaction to that described in example F4 but starting withF3 yielded 69% F6.

MS: M=580 (API+), 578 (API−)

Example F72-(3,5-dichloropyridin-4-yl)-4-(3-benzyloxyphenyl)-5-(2-methylthiopyrimidin-4-yl)-N—H-imidazole(F7)

An analogous reaction to that described in example F1 but starting withE4 yielded 66% F7.

MS: M=520 (API+), 518 (API−)

G Synthesis of the “N—H Imidazoles Sulfines” and “N—H ImidazolesSulfones” Example G12-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(2-pyridinylmethyloxy)phenyl)-5-(2-methanesulfinylpyrimidin-4-yl)-N—H-imidazole(G1)

To a solution of 1.20 g (2.1 mmol) F4 in 300 ml ethyl acetate and 50 mldichloromethane a solution of 0.70 g (3.1 mmol) m-chloroperoxybenzoicacid in 20 ml ethyl acetate was added over 10 minutes at −40° C. After 1hour at this temperature the mixture was allowed to warm up to roomtemperature and stirred overnight. The mixture was washed (saturatedaqueous NaHCO₃/saturated aqueous Na₂CO₃ 1:1) dried over MgSO₄ andevaporated to dryness to yield 1.21 g crude G1 which was used withoutfurther purification.

MS: M=596 (API+), 594 (API−)

Example G22-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(3-pyridinylmethyloxy)phenyl)-5-(2-methanesulfinylpyrimidin-4-yl)-N—H-imidazole(G2)

An analogous reaction to that described in example G1 but starting withF5 gave G2.

MS: M=596 (API+), 594 (API−)

Example G32-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(4-pyridinylmethyloxy)phenyl)-5-(2-methanesulfinylpyrimidin-4-yl)-N—H-imidazole(G3)

An analogous reaction to that described in example G1 but starting withF6 gave G3.

MS: M=596 (API+), 594 (API−)

Example G42-(3,5-dichloropyridin-4-yl)-4-(3-benzyloxyphenyl)-5-(2-methanesulfanyl-pyrimidin-4-yl)-N—H-imidazole(G4)

2.38 g (4.6 mmol) F7 were suspended in 200 ml methanol and a solution of5.62 g (9.1 mmol) Oxone™ was added at room temperature within 20minutes. After stirring at room temperature overnight the methanol wasremoved in vacuo and the residue was taken up with ethyl acetate. Theorganic layer was washed with aqueous NaHCO₃, dried over Na₂SO₄ andevaporated to dryness. The crude G4 (47%) was used without furtherpurification.

MS: M=552 (API+), 550 (API−)

H Synthesis of the “N—H Imidazoles Aminopyrimidines” Example H12-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(2-pyridinylmethyloxy)phenyl)-5-(2-hydroxypropylamino]pyrimidin-4-yl)-N-1H-imidazole(H1)

1.21 g (2.0 mmol) G1 and 3.1 g (40.6 mmol) 3-amino-1-propanol wereheated to 110° C. for 60 minutes. Purification by preparative scaleHPLC/MS on RP 18 (methanol-water-gradient) yielded 510 mg (42%) H1.

MS: M=607 (API+), 605 (API−)

Example H22-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(3-pyridinylmethyloxy)phenyl)-5-(2-[3-hydroxypropylamino]pyrimidin-4-yl)-N-1H-imidazole(H2)

An analogous reaction to that described in example H1 but starting withG2 yielded 50% H2.

MS: M=607 (API+), 605 (API−)

Example H32-(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(4-pyridinylmethyloxy)phenyl)-5-(2-[3-hydroxypropylamino]pyrimidin-4-yl)-N-1H-imidazole(H3)

An analogous reaction to that described in example H1 but starting withG3 yielded 32% H3.

MS: M=607 (API+), 605 (API−)

Example H42-(3,5-dichloropyridin-4-yl)-4-(3-benzyloxyphenyl)-5-(2-[3-hydroxypropyl-amino]pyrimidin-4-yl)-N-1H-imidazole(H4)

An analogous reaction to that described in example H1 but starting withG4 yielded 68% H4.

MS: M=547 (API+), 545 (API−)

Example I c-met Autoactivation Kinase Assay (AKA)

Assay Principle

C-met is a typical tyrosine kinase which is involved in metastasis,proliferation/apoptosis and angiogenesis of tumors. The assay is anELISA type assay measuring the phosphorylation of c-met using aphospho-tyrosine specific antibody.

Cell lysate of human colon adenocarcinoma HT29 known for its highcontent of c-met is bound to the wells of a microtiterplate (MTP) via ananti-hHGF receptor antibody (anti-hHGFR). ATP-phosphorylation of c-metis detected in presence or absence of the test compounds by using aphospho-tyrosine mouse IgG and a POD labeled goat anti-mouse IgGdetection system. Using the classical POD substrate TMB, an absorptionat 450 nm/620 nm is used to calculate enzymatic activity.

Materials:

Plates: 96-well polystyrene plates (NUNC) streptavidin-coated microtiterplates Cell line/Lysate: HT29 (ATCC HTB-38), human colon adenocarcinoma(confluence: 2.5×10⁵ cells/cm²) are washed with PBS and incubated withLysis buffer for 10 min on ice. Supernatent is collected and dilutedwith TBS. Lysate is shockfrozen in liquid nitrogen and stored at −80°C.)

Reagents (all working solutions are kept at 4° C., unless statedotherwise):

-   -   anti-hHGFR detection stock solution: 50 μg/ml (R&D Systems,        Cat.No. BAF 358) antibody final conc.: 1 μg/ml    -   p-Tyr (PY99) mouse stock solution: 200 μg/ml (Santa Cruz        Biotechnology, monoclonal IgG2b Cat.No. SC-7020) final conc.:        0.2 μg/ml    -   goat-anti-mouse IgG: 2 ml (BIO RAD, Cat.No. 170-6516)    -   (H+L)-HRP Conjugate; final conc.: 1:2000    -   Blocking Reagent: Roche Diagnostics GmbH, Cat.No.1 112589 for        ELISA diluted 1:10 in TBS    -   ATP: Adenosine-5′-triphosphate, stock solution 10 mM, stock        solution 10 mM (Roche Diagnostics GmbH, Cat.No. 127531) final        conc.: 40 μM    -   TBS: Tris-buffered saline, 50 mM TRIS pH 7.5 (Roche Diagnostics        GmbH, Cat.No. 708976), 150 mM NaCl (SIGMA, Cat.No. S-3014)    -   Wash buffer TBS-T: Tris-buffered saline, 50 mM TRIS pH 7.5 150        mM NaCl, containing 0.5% Tween20    -   Kinase buffer: Tris-buffered saline, 50 mM TRIS pH 7.5, 100 mM        NaCl, 60 mM MgCl₂ (SIGMA Chemical Company, Cat.No. M-1028)    -   Lysis buffer: 50 mM TRIS pH 7.5 containing 1% Nonidet P40 (Roche        Diagnostics GmbH, Cat.No.1754599) 0.5 % Deoxycholic acid (SIGMA        Chemical Company, Cat.No. D-6750) final conc.: 1 mM 1 mM PMSF        stock solution 70 mM (Roche Diagnostics GmbH, Cat.No.837091 40        μl/ml Complete (Roche Diagnostics GmbH, Cat.No. 1836145) Final        conc.: 40 μ/ml    -   TMB: Tetramethylbenzidine (Intergen Company, Cat.No. 91000)    -   Samples: 10 mM in DMSO (stored at −20° C.), thawed at room        temperature        Procedure:

Add 50 μl of anti-hHGFR detection antibody in blocking reagent to assayplate (final conc. 1 μg/ml), incubate assay plate for 60 min at roomtemperature on an MTP shaker.

Remove anti-hHGFR detection antibody solution from assay plate.

Add 250 μl blocking reagent per well to assay plate, incubate assayplate for 20 h, at 4° C.

Remove blocking reagent from assay plate.

Add 50 μl of HT29 lysate, incubate assay plate for 180 min, at 4° C. onan MTP shaker.

Wash assay plate with 2×200 μl TBS buffer per well.

Add 40 μl of 0.2% DMSO in kinase buffer to assay plate.

Add 40 μl sample solution (dissolved in kinase buffer—final conc. 22.5μM).

Dissolve samples (1:3 ratio) in MTP.

Add 10 μl ATP dissolved in kinase buffer (200 μM) to samples (finalconc. 40 μM ATP).

Positive control: add 40 μl kinase buffer plus 10 μl 200 μM ATP.Negative control: add 40 μl kinase buffer plus 10 μl kinase bufferwithout ATP. Incubate assay plate for 60 min at room temperature on anMTP shaker.

Wash assay plate with 2×200 μl TBS buffer and 2×200 μl blocking reagentper well.

Add 50 μl of P-Tyr (PY99) mouse monoclonal IgG_(2b) in blocking reagent(final conc. 200 ng/ml) to assay plate, incubate assay plate over nightat 4° C. on an MTP shaker.

Wash assay plate with 2×200 μl TBS buffer and 2×200 μl blocking reagentper well.

Add 50 μl of goat anti-mouse IgG (H+L)-HRP conjugate in blocking reagent(1:2000 ratio), incubate assay plate for 60 min at room temperature onan MTP shaker.

Wash assay plate with 6×2001 μl TBS-T buffer per well.

Add 50 μl TMB solution, incubate for 30 min at room temperature on anMTP shaker, add 25 μl 1 M H₂SO₄.

Measure optical density (E) at 450 nm /620 nm.

Calculate % inhibition as:1-[(E _(sample) −E _(negative control))/(E _(positive control) −E_(negative control))×100]

Agents of the invention typically have IC₅₀ values for kinase inhibitionin the range from about 1 nM to about 100 nM when tested in the aboveassay: Example IC₅₀ C-met [nM] H4 23 H1 22 H2 32 H3 54

Example K Tablet Formulation (Wet Granulation)

Item Ingredients mg/tablet 1. Compound of formula (I) 5 25 100 500 2.Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4.Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1Total 167 167 167 831Manufacturing Procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water.

2. Dry the granules at 50° C.

3. Pass the granules through suitable milling equipment.

4. Add item 5 and mix for three minutes; compress on a suitable press.

Example L Capsule Formulation

Item Ingredients mg/capsule 1. Compound of formula (I) 5 25 100 500 2.Hydrous Lactose 159 123 148 — 3. Corn Starch 25 35 40 70 4. Talc 10 1510 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600Manufacturing Procedure

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. Add items 4 and 5 and mix for 3 minutes.

3. Fill into a suitable capsule.

List of References

-   Abounader, R., et al., J. Natl. Cancer Inst. 91 (1999) 1548-1556-   Ansel et. al., Pharmaceutical Dosage Forms and Drug Delivery    Systems, 6th ed., (1995), pp. 196 and 1456-1457-   Baldwin, J. J., et al., J. Med. Chem. 22 (1979) 687-693-   Blume-Jensen, P., and Hunter, T., Nature 411 (2001) 355-365-   Gust, R., and Schoenenberg, H., Eur. J. Med. Chem. 28 (1993) 103-115-   Herynk, M. H., and Radinsky, R., In Vivo 14 (2000) 587-596-   Hubbard, S. R., et al., J. Biol. Chem. 273 (1998) 11987-11990-   Jiang, W., et al., Crit. Rev. Oncol. Hematol. 29 (1999) 209-248 J.    Med. Chem. 44 (2001) 997-   Laterra, J., et al., Lab. Invest. 76 (1997) 565-577-   Longati, P., et al., Curr. Drug Targets 2 (2001) 41-55-   Maulik, G., et al., Cytokine Growth Factor Rev. 13 (2002) 41-59-   Parr, C., and Jiang, W. G., Histol. Histopathol. 16 (2001) 251-268-   Somei, M., and Tsuchiya, M., Chem. Pharm. Bull. 29 (1981) 3145-3157-   Tomioka, D., Cancer Res. 61 (2001) 7518-7524-   Wang, R., et al., J. Cell Biol. 153 (2001) 1023-1033-   WO 01/44154-   WO 96/18626-   Zwick, E., et al., Trends Mol. Med. 8 (2002) 17-23

1. A compound of the general formula (I)

wherein W is —N═; and X is hydrogen; Y is hydrogen or a group A²-R; A²is C₁-C₅-alkylene, which may be optionally substituted by C₁-C₆-alkyl;phenyl or by hydroxy; R is selected from the group consisting ofhydroxy; linear or branched C₁-C₆-alkoxy; amino; dimethylamino;diethylamino; t-butyloxycarbonylamino; carboxyl; C₁-C₆-alkoxycarbonyl;triazolyl; cyano; piperidino; 1-pyrrolidinyl; morpholino;4-methylpiperazin-1-yl; O-A¹-NR³R⁴; S-A¹-NR³R⁴; 4-carboxyphenyl;furan-3-yl; thiophen-2-yl or 3-methylthiophen-2-yl; n is 1 or 2; and Zis one or two substituents independently selected from the groupconsisting of halogen; hydroxy; allyloxy; methyl; C₁-C₃-alkoxy, whichare optionally substituted with pyridinyl; methoxymethoxy;(2-methoxyethoxy)methyloxy; methylthio; ethoxymethoxy; methylendioxy;ethynyl; trimethylsilylethynyl and benzyloxy which is optionallysubstituted by halogen; methoxy; cyano; nitro; methylendioxy; carboxy orethoxy; or alternatively W is —CH═; and X is selected from the groupconsisting of hydrogen; OR¹; SR²; (SO)R²; (SO₂)R²;CH₂—S—CH₂—C(O)₂—CH₂—CH₃; CH₂—S—(CH₂)₂—OH or a group A¹-Q; A¹ representsa C₁-C₃-alkylene group; Q is selected from the group consisting of OR¹;SR²; SOR²; SO₂R²; NR³R⁴; NHCH₂CH₂NR³R⁴ or halogen; R¹ is selected fromthe group consisting of hydrogen; C₁-C₃-alkyl; allyl;dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;(R)-2,3-dihydroxy-1-propyl; (S)-2,3-dihydroxy-1-propyl;1,3-dihydroxy-2-propyl; 3-hydroxy-2-hydroxymethyl-1-propyl;2-methoxyethoxymethyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a groupA¹-Q¹; Q¹ is selected from the group consisting of C₁-C₂-alkoxy; cyano;carboxyl; C₁-C₆-alkoxycarbonyl; carboxamide; —CO—NR³R⁴;C₁-C₆-alkylsulfanyl; C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyl and incase that A¹ represents an 1,2-ethylen- or 1,3-propylen group, Q¹ ishydroxy or NR³R⁴; R² is selected from the group consisting ofC₁-C₆-alkyl; dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;2,3-dihydroxy-1-propyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or A¹-Q¹;R³, R⁴ are independently selected from the group consisting of hydrogen;C₁-C₆-alkyl or together form a 5 to 7 membered, saturated or unsaturatedring, optionally substituted by a methyl group and containing one or twoheteroatoms, independently selected from N or O; Y is hydrogen or agroup A²-R; A² is C₁-C₅-alkylene, which may be optionally substituted byC₁-C₆-alkyl; phenyl or by hydroxy; R is selected from the groupconsisting of hydroxy; linear or branched C₁-C₆-alkoxy; amino;dimethylamino; diethylamino; t-butyloxycarbonylamino; carboxyl;C₁-C₆-alkoxycarbonyl; triazolyl; cyano; piperidino; 1-pyrrolidinyl;morpholino; 4-methylpiperazin-1-yl; O-A¹-NR³R⁴; S-A¹-NR³R⁴;4-carboxyphenyl; furan-3-yl; thiophen-2-yl or 3-methylthiophen-2-yl; nis 1 or 2; and Z represents C₁-C₃-alkoxy, substituted with pyridinyl ifn is 1; and if n is 2, one substituent represents C₁-C₃-alkoxy,substituted with pyridinyl, and the second substituent beingindependently selected from the group consisting of halogen; hydroxy;allyloxy; methyl; C₁-C₃-alkoxy; methoxymethoxy;(2-methoxyethoxy)methyloxy; methylthio; ethoxymethoxy; methylendioxy;ethynyl; trimethylsilylethynyl; and pharmaceutically acceptable saltsthereof.
 2. The compound of claim 1, wherein W is —N═; X is hydrogen; Yis selected from the group consisting of 2-hydroxyethyl;3-hydroxypropyl; 2-methoxyethyl; 3-methoxypropyl;(R)-2,3-dihydroxy-1-propyl; (S)-2,3-dihydroxy-1-propyl;(R)-3-hydroxybutyl; (S)-3 -hydroxybutyl; 3-Hydroxy-2,2-dimethylpropyl;2-morpholinoethyl; 3-morpholinopropyl; 2-(4-methylpiperazin-1-yl)ethyl;3-hydroxy-1-phenylpropyl; 2-aminoethyl; 3-aminopropyl; 4-aminobutyl;2-(N,N-dimethylamino)ethyl; 3-(N,N-dimethylamino)propyl;3-(pyrrolidin-1-yl)propyl; CH₂COOH; (CH₂)₂COOH; (CH₂)₃COOH;CH(C₂H₅)COOH; (CH₂)₂—O—(CH₂)₂—N(CH₃)₂; (CH₂)₂—O—(CH₂)₂—NH₂;(CH₂)₂—S—(CH₂)₂—N(CH₃)₂; (CH₂)₂—S—(CH₂)₃—N(CH₃)₂;(CH₂)₃—S—(CH₂)₂—N(CH₃)₂ or (CH₂)₃—S—(CH₂)₃—N(CH₃)₂; n is 1; and Z isselected from the group consisting of 3-chloro; 4-chloro; 3-bromo;3-iodo; 3-ethynyl; 3-methoxymethoxy or 3-benzyloxy which is optionallysubstituted by halogen; methoxy; cyano; nitro; methylendioxy; carboxy orethoxy.
 3. The compound of claim 1, wherein W is —N═; X is hydrogen; Yis selected from the group consisting of 2-hydroxyethyl;3-hydroxypropyl; (R)-2,3-dihydroxy-1-propyl; (S)-2,3-dihydroxy-1-propyl;2-morpholinoethyl; 3-morpholino-propyl; 2-(4-methylpiperazin-1-yl)ethyl;2-aminoethyl; 3-aminopropyl; 2-(N,N-dimethylamino)ethyl;3-(N,N-dimethylamino)propyl or 3-(pyrrolidin-1-yl)propyl; n is 1; and Zis selected from the group consisting of 3-chloro; 4-chloro; 3-bromo;3-iodo; 3-ethynyl; 3-methoxymethoxy or 3-benzyloxy which is optionallysubstituted by halogen; methoxy or cyano.
 4. The compound of claim 3which is2-(3,5-dichloropyridin-4-yl)-4-(3-benzyloxyphenyl)-5-(2-[3-hydroxypropyl-amino]pyrimidin-4-yl)-N-1H-imidazole.5. The compound of claim 1, wherein W is —CH═; X is selected from thegroup consisting of hydrogen; OR¹; SR²; (SO)R²; (SO₂)R²;CH₂—S—CH₂—C(O)₂—CH₂—CH₃; CH₂—S—(CH₂)₂—OH or a group A¹-Q; A¹ representsa C₁-C₃-alkylene group; Q is selected from the group consisting of OR¹;SR²; SOR²; SO₂R²; NR³R⁴; NHCH₂CH₂NR³R⁴ or halogen; R¹ is selected fromthe group consisting of hydrogen; C₁-C₃-alkyl; allyl;dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;(R)-2,3-dihydroxy-1-propyl; (S)-2,3-dihydroxy-1-propyl;1,3-dihydroxy-2-propyl; 3-hydroxy-2-hydroxymethyl-1-propyl;2-methoxy-ethoxymethyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a groupA¹-Q¹; Q¹ is selected from the group consisting of C₁-C₂-alkoxy; cyano;carboxyl; C₁-C₆-alkoxycarbonyl; carboxamide; —CO—NR³R⁴;C₁-C₆-alkylsulfanyl; C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyl and incase that A¹ represents an 1,2-ethylen- or 1,3-propylen group, Q¹ ishydroxy or NR³R⁴; R² is selected from the group consisting ofC₁-C₆-alkyl; dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;2,3-dihydroxy-1-propyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or A¹-Q¹;R³, R⁴ are independently selected from the group consisting of hydrogen;C₁-C₆-alkyl or together form a 5 to 7 membered, saturated or unsaturatedring, optionally substituted by a methyl group and containing one or twoheteroatoms, independently selected from N or O; Y is hydrogen or agroup A²-R; A² is C₁-C₅-alkylene, which may be optionally substituted byC₁-C₆-alkyl; phenyl or by hydroxy; R is selected from the groupconsisting of hydroxy; linear or branched C₁-C₆-alkoxy; amino;dimethylamino; diethylamino; t-butyloxycarbonylamino; carboxyl;C₁-C₆-alkoxycarbonyl; triazolyl; cyano; piperidino; 1-pyrrolidinyl;morpholino; 4-methylpiperazin-1-yl; O-A¹-NR³R⁴; S-A¹-NR³R⁴;4-carboxyphenyl; furan-3-yl; thiophen-2-yl or 3-methylthiophen-2-yl; nis 1; and Z represents C₁-C₃-alkoxy, which are substituted withpyridinyl.
 6. The compound of claim 1, wherein W is —CH═; X is selectedfrom the group consisting of hydrogen; OR¹; SR²; (SO)R²; (SO₂)R²;CH₂—S—CH₂—-C(O)₂—CH₂—CH₃; CH₂—S—(CH₂)₂—OH or a group A¹-Q; A¹ representsa C₁-C₃-alkylene group; Q is selected from the group consisting of OR¹;CR²; SOR ; SO₂R²; NR³R⁴; NHCH₂CH₂NR³R⁴ or halogen; R¹ is selected fromthe group consisting of hydrogen; C₁-C₃-alkyl; allyl;dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;(R)-2,3-dihydroxy-1-propyl; (S)-2,3-dihydroxy-1-propyl;1,3-dihydroxy-2-propyl; 3-hydroxy-2-hydroxymethyl-1-propyl;2-methoxy-ethoxymethyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a groupA¹-Q¹; Q¹ represents C₁-C₂-alkoxy; cyano; carboxyl;C₁-C₆-alkoxycarbonyl; carboxamide; —CO—NR³R⁴; C₁-C₆-alkylsulfanyl;C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyl and in case that A¹ representsan 1,2-ethylen- or 1,3-propylen group, Q¹ is hydroxy or NR³R⁴; R² isselected from the group consisting of C₁-C₆-alkyl;dimethylphosphonylmethyl; 2,3-epoxy-1-propyl; 2,3-dihydroxy-1-propyl;2,2-dimethyl-1,3-dioxolan-4-ylmethyl or A¹-Q¹; R³, R⁴ are independentlyselected from the group consisting of hydrogen; C₁-C₆-alkyl or togetherform a 5 to 7 membered, saturated or unsaturated ring, optionallysubstituted by a methyl group and containing one or two heteroatoms,independently selected from N or O; Y is 3-hydroxypropyl; n is 1; and Zis pyridin-2-ylmethoxy; pyridin-3-ylmethoxy or pyridin-4-ylmethoxy. 7.The compound of claim 6 which are2(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(4-pyridinylmethyloxy)-phenyl)-5-(2-[3-hydroxypropylamino]pyrimidin-4-yl)-N-1H-imidazole,2(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(3-pyridinylmethyloxy)-phenyl)-5-(2-[3-hydroxypropylamino]pyrimidin-4-yl)-N-1H-imidazole,or2(2,6-dichloro-4-[2-hydroxyethoxy]phenyl)-4-(3-(2-pyridinylmethyloxy)-phenyl)-5-(2-[3-hydroxypropylamino]pyrimidin-4-yl)-N-1H-imidazole.8. A process for the manufacture of a compound of the formula

wherein W is —N═; and X is hydrogen; Y is hydrogen or a group A²-R; A²is C₁-C₅-alkylene, which may be optionally substituted by C₁-C₆-alkyl;phenyl or by hydroxy; R representsis selected from the group consistingof hydroxy; linear or branched C₁-C₆-alkoxy; amino; dimethylamino;diethylamino; t-butyloxycarbonylamino; carboxyl; C₁-C₆-alkoxycarbonyl;triazolyl; cyano; piperidino; 1-pyrrolidinyl; morpholino;4-methylpiperazin-1-yl; O-A¹-NR³R⁴; S-A¹-NR³R⁴; 4-carboxyphenyl;furan-3-yl; thiophen-2-yl or 3-methylthiophen-2-yl; n is 1 or 2; and Zrepresents is one or two substituents independently selected from thegroup consisting of halogen; hydroxy; allyloxy; methyl; C₁-C₃-alkoxy,which are optionally substituted with pyridinyl; methoxymethoxy;(2-methoxyethoxy)methyloxy; methylthio; ethoxymethoxy; methylendioxy;ethynyl; trimethylsilylethynyl and benzyloxy which is optionallysubstituted by halogen; methoxy; cyano; nitro; methylendioxy; carboxy orethoxy; or alternatively W is —CH═; and X is selected from the groupconsisting of hydrogen; OR¹; SR²; (SO)R²; (SO₂)R²;CH₂—S—CH₂—C(O)₂—CH₂—CH₃; CH₂—S—(CH₂)₂—OH or a group A¹-Q; A¹ representsa C₁-C₃-alkylene group; Q is selected from the group consisting of OR¹;SR ; SOR ; SO₂R ; NR³R⁴; NHCH₂CH₂NR³R⁴ or halogen; R¹ is selected fromthe group consisting of hydrogen; C₁-C₃-alkyl; allyl;dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;(R)-2,3-dihydroxy-1-propyl; (S)-2,3-dihydroxy-1-propyl;1,3-dihydroxy-2-propyl; 3-hydroxy-2-hydroxymethyl-1-propyl;2-methoxyethoxymethyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a groupA¹-Q¹; Q¹ representsis selected from the group consisting ofC₁-C₂-alkoxy; cyano; carboxyl; C₁-C₆-alkoxycarbonyl; carboxamide;—CO—NR³R⁴; C₁-C₆-alkylsulfanyl; C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyland in case that A¹ represents an 1,2-ethylen- or 1,3-propylen group, Q¹is hydroxy or NR³R⁴; R² is selected from the group consisting ofC₁-C₆-alkyl; dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;2,3-dihydroxy-1-propyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or A¹-Q¹;R³, R⁴ are independently selected from the group consisting of hydrogen;C₁-C₆-alkyl or together form a 5 to 7 membered, saturated or unsaturatedring, optionally substituted by a methyl group and containing one or twoheteroatoms, independently selected from N or O; Y is hydrogen or agroup A²-R; A² is C₁-C₅-alkylene, which may be optionally substituted byC₁-C₆-alkyl; phenyl or by hydroxy; R represents is selected from thegroup consisting of hydroxy; linear or branched C₁-C₆-alkoxy; amino;dimethylamino; diethylamino; t-butyloxycarbonylamino; carboxyl;C₁-C₆-alkoxycarbonyl; triazolyl; cyano; piperidino; 1-pyrrolidinyl;morpholino; 4-methylpiperazin-1-yl; O-A¹-NR³R⁴; S-A¹-NR³R⁴;4-carboxyphenyl; furan-3-yl; thiophen-2-yl or 3-methylthiophen-2-yl; nis 1 or 2; and Z represents C₁-C₃-alkoxy, substituted with pyridinyl ifn is 1; and if n is 2, one substituent represents C₁-C₃-alkoxy,substituted with pyridinyl, and the second substituent beingindependently selected from the group consisting of halogen; hydroxy;allyloxy; methyl; C₁-C₃-alkoxy; methoxymethoxy;(2-methoxyethoxy)methyloxy; methylthio; ethoxymethoxy; methylendioxy;ethynyl; trimethylsilylethynyl; and pharmaceutically acceptable saltsthereof which comprises reacting a compound of the formula

with a compound of the general formula (III)

to produce a compound of the formula

which is thereafter N-deoxygenated to produce a compound of the formula

which is thereafter oxidized via the sulphide group of the thioethers toprovide a) compounds of the general formula (VI)

which are obtained by N-deoxygenation of compounds of the generalformula (IV) whereby said compounds of the general formula (IV) areobtained by reacting a compound of the general formula (II) and b)reacting said compounds of the formulae (VI) or (VII) with a compound ofthe formula Y—NH₂ to give the compounds of formula (I); and thesubstituents W, X, Y and Z as well as n having the significance given inclaim
 1. 9. A pharmaceutical compositioncomprising a compound of theformula

wherein W is —N═; and X is hydrogen; Y is hydrogen or a group A²-R; A²is C¹-C₅-alkylene, which may be optionally substituted by C₁-C₆-alkyl;phenyl or by hydroxy; R representsis selected from the group consistingof hydroxy; linear or branched C₁-C₆-alkoxy; amino; dimethylamino;diethylamino; t-butyloxycarbonylamino; carboxyl; C₁-C₆-alkoxycarbonyl;triazolyl; cyano; piperidino; 1-pyrrolidinyl; morpholino;4-methylpiperazin-1-yl; O-A¹-NR³R⁴; S-A¹-NR³R⁴; 4-carboxyphenyl;furan-3-yl; thiophen-2-yl or 3-methylthiophen-2-yl; n is 1 or 2; and Zrepresents is one or two substituents independently selected from thegroup consisting of halogen; hydroxy; allyloxy; methyl; C₁-C₃-alkoxy,which are optionally substituted with pyridinyl; methoxymethoxy;(2-methoxyethoxy)methyloxy; methylthio; ethoxymethoxy; methylendioxy;ethynyl; trimethylsilylethynyl and benzyloxy which is optionallysubstituted by halogen; methoxy; cyano; nitro; methylendioxy; carboxy orethoxy; or alternatively W is —CH═; and X is selected from the groupconsisting of hydrogen; OR¹; SR²; (SO)R²; (SO₂)R²;CH₂—S—CH₂—C(O)₂—CH₂—CH₃; CH₂—S—(CH₂)₂—OH or a group A¹-Q; A¹ representsa C₁-C₃-alkylene group; Q is selected from the group consisting of OR¹;SR²; SOR²; SO₂R²; NR³R⁴; NHCH₂CH₂NR³R⁴ or halogen; R¹ is selected fromthe group consisting of hydrogen; C₁-C₃-alkyl; allyl;dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;(R)-2,3-dihydroxy-1-propyl; (S)-2,3-dihydroxy-1-propyl;1,3-dihydroxy-2-propyl; 3-hydroxy-2-hydroxymethyl-1-propyl;2-methoxyethoxymethyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a groupA¹-Q¹; Q¹ representsis selected from the group consisting ofC₁-C₂-alkoxy; cyano; carboxyl; C₁-C₆-alkoxycarbonyl; carboxamide;—CO—NR³R⁴; C₁-C₆-alkylsulfanyl; C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyland in case that A¹ represents an 1,2-ethylen- or 1,3-propylen group, Q¹is hydroxy or NR³R⁴; R² is selected from the group consisting ofC₁-C₆-alkyl; dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;2,3-dihydroxy-1-propyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or A¹-Q¹;R³, R⁴ are independently selected from the group consisting of hydrogen;C¹-C₆-alkyl or together form a 5 to 7 membered, saturated or unsaturatedring, optionally substituted by a methyl group and containing one or twoheteroatoms, independently selected from N or O; Y is hydrogen or agroup A²-R; A² is C₁-C₅-alkylene, which may be optionally substituted byC₁-C₆-alkyl; phenyl or by hydroxy; R represents is selected from thegroup consisting of hydroxy; linear or branched C₁-C₆-alkoxy; amino;dimethylamino; diethylamino; t-butyloxycarbonylamino; carboxyl;C₁-C₆-alkoxycarbonyl; triazolyl; cyano; piperidino; 1-pyrrolidinyl;morpholino; 4-methylpiperazin-1-yl; O-A¹-NR³R⁴; S-A¹-NR³R⁴;4-carboxyphenyl; furan-3-yl; thiophen-2-yl or 3-methylthiophen-2-yl; nis 1 or 2; and Z represents C₁-C₃-alkoxy, substituted with pyridinyl ifn is 1; and if n is 2, one substituent represents C₁-C₃-alkoxy,substituted with pyridinyl, and the second substituent beingindependently selected from the group consisting of halogen; hydroxy;allyloxy; methyl; C₁-C₃-alkoxy; methoxymethoxy;(2-methoxyethoxy)methyloxy; methylthio; ethoxymethoxy; methylendioxy;ethynyl; trimethylsilylethynyl; and pharmaceutically acceptable saltsthereof together with pharmaceutically acceptable adjuvants.
 10. Amethod of treating a disease state mediated by inhibition of c-metkinase comprising administering to a patient in need thereof atherapeutically effective amount of a compound of the formula

wherein W is —N═; and X is hydrogen; Y is hydrogen or a group A¹-R; A²is C₁-C₅-alkylene, which may be optionally substituted by C₁-C₆-alkyl;phenyl or by hydroxy; R representsis selected from the group consistingof hydroxy; linear or branched C₁-C₆-alkoxy; amino; dimethylamino;diethylamino; t-butyloxycarbonylamino; carboxyl; C₁-C₆-alkoxycarbonyl;triazolyl; cyano; piperidino; 1-pyrrolidinyl; morpholino;4-methylpiperazin-1-yl; O-A¹-NR³R⁴; S-A¹-NR³R⁴; 4-carboxyphenyl;furan-3-yl; thiophen-2-yl or 3-methylthiophen-2-yl; n is 1 or 2; and Zrepresents is one or two substituents independently selected from thegroup consisting of halogen; hydroxy; allyloxy; methyl; C₁-C₃-alkoxy,which are optionally substituted with pyridinyl; methoxymethoxy;(2-methoxyethoxy)methyloxy; methylthio; ethoxymethoxy; methylendioxy;ethynyl; trimethylsilylethynyl and benzyloxy which is optionallysubstituted by halogen; methoxy; cyano; nitro; methylendioxy; carboxy orethoxy; or alternatively W is —CH═; and X is selected from the groupconsisting of hydrogen; OR¹; SR²; (SO)R²; (SO₂)R²;CH₂—S—CH₂—C(O)₂—CH₂—CH₃; CH₂—S—(CH₂)₂—OH or a group A¹-Q; A¹ representsa C₁-C₃-alkylene group; Q is selected from the group consisting of OR¹;SR²; SOR²; SO₂R²; NR³R⁴; NHCH₂CH₂NR³R⁴ or halogen; R¹ is selected fromthe group consisting of hydrogen; C₁-C₃-alkyl; allyl;dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;(R)-2,3-dihydroxy-1-propyl; (S)-2,3-dihydroxy-1-propyl;1,3-dihydroxy-2-propyl; 3-hydroxy-2-hydroxymethyl-1-propyl;2-methoxyethoxymethyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or a groupA¹-Q¹; Q¹ representsis selected from the group consisting ofC₁-C₂-alkoxy; cyano; carboxyl; C₁-C₆-alkoxycarbonyl; carboxamide;—CO—NR³R⁴; C₁-C₆-alkylsulfanyl; C₁-C₆-alkylsulfenyl; C₁-C₆-alkylsulfonyland in case that A¹ represents an 1,2-ethylen- or 1,3-propylen group, Q¹is hydroxy or NR³R⁴; R² is selected from the group consisting ofC₁-C₆-alkyl; dimethylphosphonylmethyl; 2,3-epoxy-1-propyl;2,3-dihydroxy-1-propyl; 2,2-dimethyl-1,3-dioxolan-4-ylmethyl or A¹-Q¹;R³, R⁴ are independently selected from the group consisting of hydrogen;C₁-C₆-alkyl or together form a 5 to 7 membered, saturated or unsaturatedring, optionally substituted by a methyl group and containing one or twoheteroatoms, independently selected from N or O; Y is hydrogen or agroup A²-R; A² is C₁-C₅-alkylene, which may be optionally substituted byC₁-C₆-alkyl; phenyl or by hydroxy; R represents is selected from thegroup consisting of hydroxy; linear or branched C₁-C₆-alkoxy; amino;dimethylamino; diethylamino; t-butyloxycarbonylamino; carboxyl;C₁-C₆-alkoxycarbonyl; triazolyl; cyano; piperidino; 1-pyrrolidinyl;morpholino; 4-methylpiperazin-1-yl; O-A¹-NR³R⁴; S-A¹-NR³R⁴;4-carboxyphenyl; furan-3-yl; thiophen-2-yl or 3-methylthiophen-2-yl; nis 1 or 2; and Z represents C₁-C₃-alkoxy, substituted with pyridinyl ifn is 1; and if n is 2, one substituent represents C₁-C₃-alkoxy,substituted with pyridinyl, and the second substituent beingindependently selected from the group consisting of halogen; hydroxy;allyloxy; methyl; C₁-C₃-alkoxy; methoxymethoxy;(2-methoxyethoxy)methyloxy; methylthio; ethoxymethoxy; methylendioxy;ethynyl; trimethylsilylethynyl; and pharmaceutically acceptable saltsthereof
 11. The method of claim 10 wherein the disease is cancer.